By Karuna Jaggar, Executive Director

On Tuesday before SABCS officially opened, one provider joked about the eager anticipation surrounding the KATHERINE Trial: “It’s like Christmas Eve, will we be able to sleep tonight?”

In addition to the KATHERINE study (GS1-10), the IMpassion 130 study (GS1-04) is being touted as establishing a new standard of care. I’ll discuss both here.

IMpassion 130                                                                         

As I wrote in a previous blog, the IMpassion 130 study (GS1-04) tests newly diagnosed metastatic triple negative breast cancer (TNBC) patients for PD-L1 expression in order to identify patients who may benefit from combined therapy of the immunotherapy atezolizumab (trade nameTecentriq) in combination with nab-paclitaxel (Abraxane).

Atezolizumab is an immunotherapy made by Genentech/Roche that targets PD-L1. Nab-paclitaxel (Abraxane) is an injectable formulation of the chemotherapy paclitaxel, also known as “nanoparticle albumin–bound paclitaxel.”

The study focused on previously untreated metastatic or inoperable locally advanced TNBC. 902 patients randomized to receive first-line atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel until unacceptable toxicity or disease progression. Progression free survival (PFS) and overall survival (OS) were two of four pre-specified co-primary endpoints for the study. This is the first interim overall survival analysis looking at PD-L1+ patients.

PD-L1 immune cell positive is a predictive biomarker that the researchers were able to show successfully identifies patients who clinically benefit from atezolizumab and nab-paclitaxel. Patients with PD-L1 expression experienced a significant improvement in clinically meaningful progression free survival (PFS) and overall survival (OS).

For PD-L1+ patients, the median PFS in the atezolizumab group was 7.5 months compared with 5.0 months with placebo and OS was 25 months in the atezolizumab group compared with 15.5 months in the placebo group 

In establishing PD-L1 as a predictive biomarker for identifying untreated metastatic TNBC patients who benefit from immunotherapy, the researchers established that 1 percent or more of PD-L1+ immune cells predicts benefit of combined therapy. There was no treatment benefit for patients with no PD-L1 immune cell expression.


The KATHERINE study (GS1-10) showed that patients with early stage HER2+ breast cancer, whose tumors did not disappear after systemic therapy (chemotherapy and trastuzumab (Herceptin) before surgery, experienced improved disease-free survival on T-DM1 rather than Herceptin.

T-DM1 is what people commonly call ado-trastuzumab emtansine (Kadcyla). It’s an antibody–drug conjugate of trastuzumab and the chemotherapy emtansine (DM1), with the idea that chemo can be more effectively delivered to the cancer cells when delivered by Herceptin, which binds to the HER2 receptor, which is only over-expressed in cancer cells. It was approved by the FDA in early 2013.

Because HER2+ disease is aggressive, patients are often given systemic therapy before surgery. Researchers have shown that patients whose cancers respond to neoadjuvant (before surgery) treatment, do better. But the question too often is what to do for patients with an aggressive HER2+ breast cancer that did not respond fully to neoadjuvant therapy, since we know these patients are at risk for a recurrence and metastasis. The researchers wanted to know if substituting TDM-1 for Herceptin, would improve outcomes.

KATHERINE was a multicenter, randomized, open-label, phase 3 trial led by the German Breast Group, the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, independent investigators, and the sponsor (La Roche/Genentech). Eligible patients had HER2+ early breast cancer with residual disease after neoadjuvant treatment. All participants got at least 6 cycles of chemotherapy (anthracycline for 76%) and 9 weeks of Herceptin. The median age was 49 and three-fourths of patients were white. Between April 2013 and December 2015, 1486 participants were randomly assigned to receive T-DM1 or trastuzumab as adjuvant therapy every 3 weeks for 14 cycles.

Invasive disease-free survival (IDSF) was the primary endpoint, which is the length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer. Median follow up at interim analysis 41 months.

The three-year estimated invasive disease-free survival (IDFS) was 88.3 percent for women on T-DM1 versus 77 percent for women taking trastuzumab (Herceptin), and this IDFS benefit was seen across key patient subgroups. 199 patients had distant recurrence, 121 in the Herceptin vs 78 in the T-DM1 arm. There were 98 deaths, 56 in Herceptin and 42 in T-DM1, but because this is an early analysis, the data is not statistically significant and will need additional follow up. Unfortunately, T-DM1 did not have an effect on brain metastases.

Despite being called “well tolerated” by some providers at the conference who are excited by the new options this study offers for patients, T-DM1 is toxic and comes with a black box warning from the FDA. There were a wide range of adverse events reported in the study and T-DM1 clearly has worse overall toxicity compared to Herceptin. The most common grade three or worse adverse effects included decreased platelet count (5.7% with T-DM1 vs 0.3% with trastuzumab), hypertension (2.0% vs 1.2%, respectively), peripheral sensory neuropathy (1.4% vs 0), decreased neutrophil count (1.2% vs 0.7%), hypokalemia (1.2% vs 0.1%), fatigue (1.1% vs 0.1%), and anemia (1.1% vs 0.1%). 133 (18%) of patients receiving T-DM1 stopped treatment because of side effects compared to 14 (2.1%) in the trastuzumab arm. One person died from treatment-related adverse event on T-DM1.

The cost of treatment was not discussed in the presentation. When T-DM1 was first approved, 1 cycle (which is repeated every 21 days) cost $9800. At the time, it seemed exorbitant, but costs of new cancer treatments have only continued to rise. We continue to recognize the “financial toxicity” of treatment, as well as the physical toll.

The KATHERINE study was warmly received and T-DM1 is now being considered a new standard of care, opening the door to the use of neoadjuvant therapy for HER2+ early stage breast cancer.

The question from patients: is this good enough to get a good nights’ sleep or should we refuse to rest until we have much more?